Approaches for Reactive Oxygen Species and Oxidative Stress Quantification in Epilepsy

Olowe, Rhoda; Sandouka, Sereen; Saadi, Aseel; Shekh‐Ahmad, Tawfeeq

doi:10.3390/antiox9100990

Cited by 63 publications

(39 citation statements)

References 176 publications

(223 reference statements)

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“…Three ferroptosis markers were analyzed in blood of children with epilepsy: two by-products of lipid peroxidation (4-HNE, 15(S)-HETE) and GSH, the main antioxidant in cells, which displays dual actions, as a direct ROS scavenger and as co-factor in many detoxifying enzymes [ 4 ]. As shown in Figure 1 A, the 4-HNE content was significantly increased in plasma of children with epilepsy (3.51 ± 0.64 µg/mL vs. 0.98 ± 0.32 healthy subjects, p < 0.01, 95% confidence interval = −4.252 to −0.8246), whereas the level of 15(S)-HETE, the principal metabolite produced by the arachidonate peroxidation, was comparable to controls (1967 ± 246 pg/mL vs. 2685 ± 350 pg/mL of healthy subjects, Figure 1 B).…”

Section: Resultsmentioning

confidence: 99%

“…Oxidative stress, glutamate-mediated excitotoxicity and neuroinflammation underlie the neurobiology of epilepsy, leading to seizure-induced cell death, increased susceptibility to neuronal synchronization, and progressive degeneration of brain areas [ 1 , 2 , 3 , 4 ]. Oxidative stress markers are increased in patients with status epilepticus (SE), correlating with severity, brain MRI, and outcome [ 1 , 2 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Imbalance of Systemic Redox Biomarkers in Children with Epilepsy: Role of Ferroptosis

et al. 2021

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To assess if ferroptosis, a new type of programmed cell death accompanied by iron accumulation, lipid peroxidation, and glutathione depletion, occurs in children with epilepsy, and in order to identify a panel of biomarkers useful for patient stratification and innovative-targeted therapies, we measured ferroptosis biomarkers in blood from 83 unrelated children with a clinical diagnosis of epilepsy and 44 age-matched controls. We found a marked dysregulation of three ferroptosis key markers: a consistent increase of 4-hydroxy-2-nonenal (4-HNE), the main by-product of lipid peroxidation, a significant decrease of glutathione (GSH) levels, and a partial inactivation of the enzyme glutathione peroxidase 4 (GPX4), the mediator of lipid peroxides detoxification. Furthermore, we found a significant increase of NAPDH oxidase 2 (NOX2) in the blood of children, supporting this enzyme as a primary source of reactive oxygen species (ROS) in epilepsy. Additionally, since the nuclear factor erythroid 2-related factor 2 (NRF2) induction protects the brain from epileptic seizure damage, we also evaluated the NRF2 expression in the blood of children. The antioxidant and anti-inflammatory transcription factor was activated in patients, although not enough to re-establish a correct redox homeostasis for counteracting ferroptosis. Ferroptosis-mediated oxidative damage has been proposed as an emergent mechanism underlying the pathogenesis of epilepsy. Overall, our study confirms a crucial role for ferroptosis in epilepsy, leading to the identification of a panel of biomarkers useful to find new therapeutic targets. Developing innovative drugs, which act by inhibiting the ferroptosis signaling axis, may represent a promising strategy for new anti-seizure medications.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Imbalance of Systemic Redox Biomarkers in Children with Epilepsy: Role of Ferroptosis

et al. 2021

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“…Reactive oxygen species (ROS) are highly reactive metabolites of oxygen with a very short lifetime (from ns to s) in the biological system [ 24 ]. Among all, the most common free radicals obtained as by-products of cellular aerobic metabolism are hydroxyl (OH˙) and superoxide (O 2 ˉ˙) [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

Selective Binding and Redox-Activity on Parallel G-Quadruplexes by Pegylated Naphthalene Diimide-Copper Complexes

et al. 2021

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G-quadruplexes (G4s) are higher-order supramolecular structures, biologically important in the regulation of many key processes. Among all, the recent discoveries relating to RNA-G4s, including their potential involvement as antiviral targets against COVID-19, have triggered the ever-increasing need to develop selective molecules able to interact with parallel G4s. Naphthalene diimides (NDIs) are widely exploited as G4 ligands, being able to induce and strongly stabilize these structures. Sometimes, a reversible NDI-G4 interaction is also associated with an irreversible one, due to the cleavage and/or modification of G4s by functional-NDIs. This is the case of NDI-Cu-DETA, a copper(II) complex able to cleave G4s in the closest proximity to the target binding site. Herein, we present two original Cu(II)-NDI complexes, inspired by NDI-Cu-DETA, differently functionalized with 2-(2-aminoethoxy)ethanol side-chains, to selectively drive redox-catalyzed activity towards parallel G4s. The selective interaction toward parallel G4 topology, controlled by the presence of 2-(2-aminoethoxy)ethanol side chains, was already firmly demonstrated by us using core-extended NDIs. In the present study, the presence of protonable moieties and the copper(II) cavity, increases the binding affinity and specificity of these two NDIs for a telomeric RNA-G4. Once defined the copper coordination relationship and binding constants by competition titrations, ability in G4 stabilization, and ROS-induced cleavage were analyzed. The propensity in the stabilization of parallel topology was highlighted for both of the new compounds HP2Cu and PE2Cu. The results obtained are particularly promising, paving the way for the development of new selective functional ligands for binding and destructuring parallel G4s.

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“…Epilepsy can cause the activation and proliferation of microglia and astrocytes, which are involved in various pathological processes such as in ammation and apoptosis in central system diseases [32,33] . At the same time, epileptic seizures will increase oxidative stress and promote the production of reactive oxygen species, leading to excessive neuronal excitement, oxidative damage, cells apoptosis and long-term intracranial biochemical changes [34,35] . Therefore, it is believed that the in ammatory and oxidative stress responses are the underlying mechanisms of epilepsy neuropathology.…”

Section: Discussionmentioning

confidence: 99%

Genistein Protects Epilepsy-Induced Brain Injury Through Regulating The JAK2/STAT3 and Keap1/Nrf2 Signaling Pathways in The Developing Rats

Huang

Feng

et al. 2021

Preprint

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Background: Epilepsy is a common chronic neurological disease caused by the over-synchronization of neurons that lead to brain dysfunction. Recurrent seizures or status epilepticus can cause irreversible brain damage. The JAK2-STAT3 signal transduction pathway is stimulated by cytokines and involved in various pathological processes including inflammation, apoptosis and immune regulation in central system diseases. Keap1/Nrf2 is an important anti-oxidative stress pathway, which can reduce the toxic effects of oxygen free radicals and endogenous toxins on neurons. Genistein (Gen) can modulate inflammation and neuronal apoptosis, and may thereby have antiepileptic effects. This study aimed to explore the regulation of Genistein on JAK2/STAT3 and Keap1/Nrf2 signaling pathway and the protective effects on brain injury after epilepsy. Methods: Pentylenetetrazole (PTZ) was used to induce epilepsy in developing rats and Genistein was used for pretreatment of epilepsy. The seizure latency, grade scores and duration of the first generalized tonic-clonic seizure (GTCs) were recorded. Hippocampus tissue was sampled at 24 hours post-epilepsy. Immunofluorescence staining was used to observe the number of mature neurons, activated microglia and astrocytes in the hippocampal CA1 region. Western blot and qRT-PCR were used to determine the protein and mRNA levels of p-JAK2, p-STAT3, TNF-α, IL-1β, Keap1, Nrf2, HO-1, NQO1, caspase3, Bax and Bcl2 in the hippocampus. Results: Immunofluorescence showed that the number of neurons significantly decreased, and activated microglia and astrocytes significantly increased after epilepsy; Western blot and q-PCR showed that the expressions of p-JAK2, p-STAT3, TNF-α, IL-1β, Keap1, caspase3 and Bax significantly increased, while Nrf2, HO-1, NQO1 and Bcl-2 were significantly reduced after epilepsy. These effects were reversed by Genistein treatment. Moreover, Genistein was found to prolong seizure latency and reduce seizure intensity score and duration of generalized tonic-clonic seizures(GTCs). Conclusions: Genistein can activate the Keap1/Nrf2 antioxidant stress pathway and attenuate the activation of microglia and astrocytes. Genistein also inhibits the JAK2-STAT3 inflammation pathway and expression of apoptotic proteins, and increases the number of surviving neurons, thus having a protective effect on epilepsy-induced brain damage.

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Approaches for Reactive Oxygen Species and Oxidative Stress Quantification in Epilepsy

Cited by 63 publications

References 176 publications

Imbalance of Systemic Redox Biomarkers in Children with Epilepsy: Role of Ferroptosis

Imbalance of Systemic Redox Biomarkers in Children with Epilepsy: Role of Ferroptosis

Selective Binding and Redox-Activity on Parallel G-Quadruplexes by Pegylated Naphthalene Diimide-Copper Complexes

Genistein Protects Epilepsy-Induced Brain Injury Through Regulating The JAK2/STAT3 and Keap1/Nrf2 Signaling Pathways in The Developing Rats

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